ZA-II-05, a novel NMDA-receptor antagonist reverses vanadium-induced neurotoxicity in Caenorhabditis elegans (C. elegans).

INTRODUCTION: Vanadium is a widely used transition metal in industrial applications, but it also poses significant neurotoxic and environmental risks. Previous studies have shown that exposure to vanadium may lead to neurodegenerative diseases and neuropathic pain, raising concerns about its impact on human health and the ecosystem. To address vanadium neurotoxicity, through targeting NMDA glutamate and dopamine signaling, both involved in neurodegenerative disorders, shows promise. Using Caenorhabditis elegans as a model, we evaluated a novel compound with a mixed NMDA glutamate receptor-dopamine transporter pharmacology, ZA-II-05 and found it effectively ameliorated vanadium-induced neurotoxicity, suggesting a potential neuroprotective role. METHODS: Synchronized young adult worms were assigned to four different experimental groups; Controls; 100 mM of Vanadium; Vanadium and 1 mg/ml ZA-II-05; and ZA-II-05 alone. These were examined with different markers, including DAPI, MitoTracker Green and MitoSox stains for assessment of nuclei and mitochondrial density and oxidative stress, respectively. RESULTS: Exposure to vanadium in C. elegans resulted in decreased nuclear presence and reduction in mitochondrial content were also analyzed based on fluorescence in the pharyngeal region, signifying an increase in the production of reactive oxygen species, while vanadium co-treatment with ZA-II-05 caused a significant increase in nuclear presence and mitochondrial content. DISCUSSION: Treatment with ZA-II-05 significantly preserved cellular integrity, exhibiting a reversal of the detrimental effects induced by vanadium by modulating and preserving the normal function of chemosensory neurons and downstream signaling pathways. This study provides valuable insights into the mechanisms of vanadium-induced neurotoxicity and offers perspectives for developing therapeutic interventions for neurodegenerative diseases related to environmental toxins.

Design, synthesis and anticancer/antiestrogenic activities of novel indole-benzimidazoles.

Indole-benzimidazoles have recently gained attention due to their antiproliferative and antiestrogenic effects. However, their structural similarities and molecular mechanisms shared with selective estrogen receptor modulators (SERMs) have not yet been investigated. In this study, we synthesized novel ethylsulfonyl indole-benzimidazole derivatives by substituting the first (R1) and fifth (R2) positions of benzimidazole and indole groups, respectively. Subsequently, we performed 1H NMR, 13C NMR, and Mass spectral and in silico docking analyses, and anticancer activity screening studies of these novel indole-benzimidazoles. The antiproliferative effects of indole-benzimidazoles were found to be more similar between the estrogen (E2) responsive cell lines MCF-7 and HEPG2 in comparison to the Estrogen Receptor negative (ER-) cell line MDA-MB-231. R1:p-fluorobenzyl group members were selected as lead compounds for their potent anticancer effects and moderate structural affinity to ER. Microarray expression profiling and gene enrichment analyses (GSEA) of the selected compounds (R1:p-fluorobenzyl: 48, 49, 50, 51; R1:3,4-difluorobenzyl: 53) helped determine the similarly modulated cellular signaling pathways among derivatives. Moreover, we identified known compounds that have significantly similar gene signatures to that of 51 via queries performed in LINCS database; and further transcriptomics comparisons were made using public GEO datasets (GSE35428, GSE7765, GSE62673). Our results strongly demonstrate that these novel indole-benzimidazoles can modulate ER target gene expression as well as dioxin-mediated aryl hydrocarbon receptor and amino acid deprivation-mediated integrated stress response signaling in a dose-dependent manner.

Pioneering the Battle Against Breast Cancer: The Promise of New Bcl-2 Family.

Currently, breast cancer is the most common cancer type, accounting for 1 in every 4 cancer cases. Leading both in mortality and incidence, breast cancer causes 1 in 4 cancer deaths. To decrease the burden of breast cancer, novel therapeutic agents which target the key hallmarks of cancer, are being explored. The Bcl-2 family of proteins has a crucial role in governing cell death, making them an attractive target for cancer therapy. As cancer chemotherapies lead to oncogenic stress, cancer cells upregulate the Bcl-2 family to overcome apoptosis, leading to failure of treatment. To fix this issue, Bcl-2 family inhibitors, which can cause cell death, have been introduced as novel therapeutic agents. Members of this group have shown promising results in in-vitro studies, and some are currently in clinical trials. In this review, we will investigate Bcl-2 family inhibitors, which are already in trials as monotherapy or combination therapy for breast cancer, and we will also highlight the result of in vitro studies of novel Bcl-2 family inhibitors on breast cancer cells. The findings of these studies have yielded encouraging outcomes regarding the identification of novel Bcl-2 family inhibitors. These compounds hold significant potential as efficacious agents for employment in both monotherapy and combination therapy settings.

Targeting Bcl-2 with Indole Scaffolds: Emerging Drug Design Strategies for Cancer Treatment.

The B-cell lymphoma-2 (Bcl-2) protein family plays a crucial role as a regulator in the process of apoptosis. There is a substantial body of evidence indicating that the upregulation of antiapoptotic Bcl-2 proteins is prevalent in several cancer cell lines and original tumour tissue samples. This phenomenon plays a crucial role in enabling tumour cells to avoid apoptosis, hence facilitating the development of resistant cells against chemotherapy. Therefore, the success rate of chemotherapy for cancer can be enhanced by the down-regulation of anti-apoptotic Bcl-2 proteins. Furthermore, the indole structural design is commonly found in a variety of natural substances and biologically active compounds, particularly those that possess anti-cancer properties. Due to its distinctive physicochemical and biological characteristics, it has been highly regarded as a fundamental framework in the development and production of anti-cancer drugs. As a result, a considerable range of indole derivatives, encompassing both naturally occurring and developed compounds, have been identified as potential candidates for the treatment of cancer. Several of these derivatives have advanced to clinical trials, while others are already being used in clinical settings. This emphasizes the significant role of indole in the field of research and development of anti-cancer therapeutics. This study provides an overview of apoptosis and the structural characteristics of Bcl-2 family proteins, and mainly examines the present stage and recent developments in Bcl-2 inhibitors with an indole scaffold embedded in their structure.

Synthesis, Anticancer Activity, and In Silico Modeling of Alkylsulfonyl Benzimidazole Derivatives: Unveiling Potent Bcl-2 Inhibitors for Breast Cancer.

A series of alkylsulfonyl 1H-benzo[d]imidazole derivatives were synthesized and evaluated for anticancer activity against human breast cancer cells, MCF-7 in vitro. The cytotoxic potential was determined using the xCELLigence real-time cell analysis, and expression levels of genes related to microtubule organization, tumor suppression, apoptosis, cell cycle, and proliferation were examined by quantitative real-time polymerase chain reaction. Molecular docking against Bcl-2 was carried out using AutoDock Vina, while ADME studies were performed to predict the physicochemical and drug-likeness properties of the synthesized compounds. The results revealed that compounds 23 and 27 were the most potent cytotoxic derivatives against MCF-7 cells. Gene expression analysis showed that BCL-2 was the most prominent gene studied. Treatment of MCF-7 cells with compounds 23 and 27 resulted in significant downregulation of the BCL-2 gene, with fold changes of 128 and 256, respectively. Docking analysis predicted a strong interaction between the compounds and the target protein. Interestingly, all of the compounds exhibit a higher binding affinity toward Bcl-2 than the standard drug (compound 27 vina score = -9.6 kcal/mol, vincristine = -6.7 kcal/mol). Molecular dynamics simulations of compounds 23 and 27 showed a permanent stabilization in the binding site of Bcl-2 for 200 ns. Based on Lipinski and Veber's filters, all synthesized compounds displayed drug-like characteristics. These findings suggest that compounds 23 and 27 were the most promising cytotoxic compounds and downregulated the expression of the BCL-2 gene. These derivatives could be further explored as potential candidates for the treatment of breast cancer.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

Cyclin-Dependent Kinase 4/6 Inhibitors Against Breast Cancer.

Breast cancer is the most frequently diagnosed and leading cause of cancer-related deaths in women worldwide. Based on global cancer (GLOBOCAN) 2020 statistics, 1 in 4 cancer cases and 1 in 6 cancer deaths are attributable to breast cancer, leading both in incidence and mortality. To address the increasing burden of cancer, novel therapeutic approaches that target key hallmarks of cancer are explored in cancer drug discovery. Cyclin-dependent kinase (CDK) inhibitors are generally purine and pyrimidine analogues validated for the treatment of cancer due to their unique roles in cancer deregulation and novel therapeutic potentials. So far, three orally administered, potent and highly selective CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have been approved by the FDA for the targeted treatment of advanced or metastatic breast cancer in combination with endocrine therapy. Furthermore, several compounds derived from various synthetic scaffolds are being explored with promising results and positive outcomes in various stages of clinical trials. In this review, we highlight these CDK4/6 inhibitor compounds with potent anti-CDK4/6, in vitro and in vivo activities on breast cancer cells. With the remarkable prospects of these compounds, there is great optimism further novel CDK inhibitor compounds will be discovered in the future that could boost therapeutic options for cancer treatment.

Benzimidazoles Against Certain Breast Cancer Drug Targets: A Review

BACKGROUND: Benzimidazoles are widely used scaffolds against various types of cancer, including breast cancer. To this end, anticancer agents must be developed using the knowledge of the specific targets of BC. OBJECTIVE: In this study, we aim to review the compounds used against some of the biomolecular targets of breast cancer. To this end, we present information about the various targets, with their latest innovative studies. CONCLUSION: Benzimidazole ring is an important building block that can target diverse cancer scenarios since it can structurally mimic biomolecules in the human body. Additionally, many studies imply the involvement of this moiety on a plethora of pathways and enzymes related to BC. Herein, our target- based collection of benzimidazole derivatives strongly suggests the utilization of benzimidazole derivatives against BC.

Synthesis, antioxidant activity, molecular docking and ADME studies of novel pyrrole-benzimidazole derivatives.

Several 5-(alkylsulfonyl)-1-substituted-2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole derivatives were synthesized and their antioxidant activities were investigated using lipid peroxidation (LPO) and 7-ethoxyresorufin O-deethylase (EROD) assays. Docking analysis with Human NAD[P]H-Quinone oxidoreductase 1 (NQO1) was also performed to gather thorough information about these compounds that have antioxidant activities. Moreover, their molecular descriptors and ADME properties were calculated using the SwissADME online program. As a result, most of our compounds possessed better affinity and created ample interactions with NQO1. The most potent compound 5j had LP inhibition value of 3.73 nmol/mg/min. Other compounds exhibited moderate activity on LP levels comparing to standard butylated hydroxy toluene (BHT). However, the inhibitory effect on EROD activity was not significant.

Synthesis, Molecular Docking Studies and Antibacterial Activities of Novel Monocationic Indole-benzimidazole Derivatives.

BACKGROUND: Finding efficient therapy against hospital-acquired MRSA infections has become rather important in the last decade. To this end, inhibition of the enzyme pyruvate kinase (PK) is being investigated for antibacterial activity, since this enzyme controls energy generation and metabolic flux distribution. Our main scaffold consists of benzimidazole and indole rings fused together. Both rings are famous for antibacterial properties and promising anti-MRSA compounds including indole ring. METHODS: Several 1-substituted-2-(1H-indol-3-yl)-N-substituted-1H-benzimidazole-5-carboxamidine analogues were developed, synthesized and their antibacterial activities were evaluated against Staphylococcus aureus (ATCC 25923), Methicillin resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Staphylococcus epidermidis (ATCC 12228) by using tube dilution method. Molecular docking analysis with a characteristic protein called MRSA- Pyruvate Kinase has been conducted for the assessment of the activities of our compounds against Methicillinresistant S. aureus (MRSA). RESULTS: Among all the tested compounds, the most potent compound 36 had MIC values as 3.12, 3.12 and 6.25 µg/mL against S. aureus, Methicillin-resistant S. aureus (MRSA), and S. epidermidis, respectively. This compound had much better docking energy value than standard ampicillin and also created the link between two residues in different monomers of PK. DISCUSSION: This approach of using indol-amidine conjugate systems as anti-MRSA agents may include MRSA-PK as potential target. To further increase the affinity, some other H-bonding parts may be added. By doing so, another bridge with Ile361 residues on both sides can be created. Our compounds tend to violate log P limit of Lipinski, therefore some optimizations with formulation can be made. CONCLUSION: This study mainly includes the design, synthesis and optimization of indolebenzimidazole- amidine derivatives. Docking studies confirmed our results, since our most potent hit compound 36 created the necessary interactions between two chains of MRSA-PK. Further optimization can be considered to increase drug ability.

Bicycloheptylamine-Doxorubicin Conjugate: Synthesis and Anticancer Activities in σ2 Receptor-Expressing Cell Lines.

BACKGROUND: Novel bicycloheptylamines were designed and synthesized. These compounds were found to be selective for sigma-2 receptors. These receptors have been found to be up to 10 fold over-expressed in certain cancer cell lines, leading to investigation of possible uses as a biomarker in diagnosis and/or treatment especially in cancers with poor prognosis. OBJECTIVES: The aim was to conjugate a novel sigma-2 receptor ligand to doxorubicin to examine anticancer activities, with and without conjugation, and therefore possibilities in drug delivery. METHODS: Conjugation was conducted using N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide HCl as a coupling agent. Affinity towards the sigma-2 receptor was tested using ligand-receptor binding studies. Anticancer activities against cancer cell lines were carried out using cell viability assays. Caspase dependency was tested using Z-VAD-FMK, a pan-caspase inhibitor, to begin to investigate mechanisms of action. RESULTS: The target compound retained affinity towards the sigma-2 receptor and exhibited potent anticancer activities on cancer cell lines expressing the sigma-2 receptor. The potencies exceeded those of doxorubicin, the lead sigma-2 receptor ligand, as well as non-covalent combination of both drugs. The activity was also found to be caspase-dependent. CONCLUSION: The conjugation of target bicycloheptylamines with cytotoxic moieties may yield potent and selective molecules for detection and/or treatment of certain cancers.

Synthesis and antimicrobial evaluation of some new substituted purine derivatives.

A series of 8,9-disubstituted adenines (4, 5, 8), 6-substituted aminopurines (10-13) and 9-(p-fluorobenzyl/cyclopentyl)-6-substituted aminopurines (16, 17, 19-30) have been prepared and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolate), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. 6-[(N-phenylaminoethyl)amino]-9H-purine (12) which has no substitution at N-9 position and 9-cyclopentyl-6-[(4-fluorobenzyl)amino]-9H-purine (24) exhibited excellent activity against C. albicans with MIC 3.12 microg/mL. These compounds displayed better antifungal activity than that of standard oxiconazole. Furthermore, compound 22 carrying 4-chlorobenzylamino group at the 6-position of the purine moiety exhibited comparable antibacterial activity with that of the standard ciprofloxacin against both of the drug-resistant bacteria (MRSA, standard and clinical isolate).

Antimicrobial activities of some tetrahydronaphthalene-benzimidazole derivatives.

Novel retinoid derivatives containing a benzimidazole moiety were synthesized and tested for their antimicrobial activity. Their antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida krusei and Candida albicans were evaluated. While some of the compounds exhibited moderate activity against MRSA, S. aureus, E. faecalis, C. krusei and C. albicans, none of the compounds showed activity against E. coli and P. aeruginosa.

Antimicrobial Activities of 1-H-Benzimidazole-based Molecules.

Benzimidazole is a heterocyclic aromatic organic compound which has been an important pharmacophore and privileged structure in medicinal chemistry. Substituted benzimidazoles have considerable interest as compounds with a wide spectrum of biological activity and low toxicity. Benzimidazole derivatives are structurally related to purine nucleoside bases, which allow them to interact easily with the biopolymers of the living systems. Different substituted benzimidazoles have an extensive range of biological activities including: antiviral, antifungal, antimicrobial, antiprotozoal, antiinflammatory, anticancer, antioxidant, anticoagulant, antidiabetic and antihypertensive activities. Infectious diseases are those whose incidence in humans has increased during the past few decades. They cause suffering and death and an enormous financial burden. Antimicrobial drugs have saved the lives of millions of people. However, the dramatic increase in drug-resistant microbes is threatening to reverse medical progress of the past 50 years. Benzimidazoles are very effective compounds with respect to their bacteria inhibitory activity. Biochemical and pharmacological studies have showed that these molecules are effective against various strains of microorganisms. Some benzimidazole compounds inhibit the biosynthesis of ergosterol, required in the cell membrane of fungi and protozoa and a useful target for antifungal drugs. The result of many efforts to develop new molecules for effective antimicrobials reveals that the benzimidazoles are still one of the most versatile class of compounds against microbes.

Antioxidant activities of retinoidal benzimidazole or indole derivatives in in vitro model systems.

The antioxidants and antioxidant enzyme systems belong to the major protective systems of the organism. The use of retinoic acid in many animal models of carcinogenesis has also suggested that its action may depend on its antioxidant activity. Retinoids have been shown to function as effective antioxidants by inhibiting microsomal lipid peroxidation. The importance of antioxidants for the maintenance of health and for protection from oxidative stressinduced damage places them in the forefront of mechanistic approaches to genetically originated diseases related to retinoids. It is well known that cellular and subcellular membranes are susceptible to lipid oxidation because of their relatively high concentration of polyunsaturated fatty acids and their close proximity to oxygen, transition metals and peroxidases. Therefore, there has been a great deal of interest in the study of reactive oxygen species (ROS) which are associated with arteriosclerosis, nephritis and carcinogenesis. Antioxidants scavenge and prevent the formation of free radicals so they are highly important for the treatment of these kinds of diseases. For this reason, antioxidant properties of retinoidal benzimidazole or indole derivatives have been investigated in this review.

NMDA Receptor Antagonists for Treatment of Depression.

Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors.

Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer's disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 µM and IC50 values above 150 µM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.

Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.

As part of our program to explore the influence of small structural modifications of our drug candidate 3ß-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3ß-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3ß-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 µM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.

Syntheses and in vitro anticancer properties of novel radiosensitizers.

Series of 4-(ethylsulfonyl)-1-halogen-2-nitrobenzene (3a-e) and 1-(4-halogen-3-nitrophenyl) propan-1-one (5a-d) analogs designed as novel radiosensitizers using bromonitropropiophenone and bromonitrobenzonitrile as lead compounds were synthesized. The anticancer activities of the compounds were evaluated in vitro using human prostate cancer (DU-145) and breast cancer (MCF-7) cell lines and the MTT assay. From the series, six compounds (3b-e, 5b-c) exhibited potent growth inhibitory effects against both cell lines. The most active, compound 3d, is an iodosulfone and is significantly more potent than the lead compound 5c at 10 µm. Compounds were then compared with doxorubicin, a clinically used anticancer compound for breast and prostate cancers. Our most active compound 3d is more effective than doxorubicin at the dose level of 10 µm at 3 days after radiation, cell viabilities of 18%, 13% compared to 87%, 94% against MCF-7, and 15%, 20% compared to 60%, 75% against DU-145 without and with radiation, respectively. At 10 µm, compound 5c had no effects as compared to control, whereas compound 3d reduced DU-145 cell viability to 16% and that of MCF-7 cells to 9% even at 5 days after radiation. These results are very encouraging. Future studies include testing the compounds in vivo with and without radiation.

Syntheses and pharmacological evaluations of novel N-substituted bicyclo-heptane-2-amines at N-methyl-D-aspartate receptors.

Several novel norcamphor (bicycloheptane)-based compounds were designed and synthesized as non-competitive N-methyl-D-aspartate receptor antagonists at the phencyclidine binding sites. The heterocyclic ring was also varied to examine piperidine, pyrrolidine, and morpholine groups. We examined pharmacological activities of these compounds in vitro (binding studies) and in vivo (maximal electroshock test). Pharmacological evaluations revealed one of the compounds, 5a, to be a good lead, exhibiting moderate binding at N-methyl-D-aspartate receptors (IC(50) =7.86 µm; K(i) =5.28 µm), maximal electroshock neuroprotection activity at 100 mg/kg and acceptable toxicity profile.